Environmental and behavioral factors can modulate baseline breast cancer risk, both in humans and in animal models. One of the most difficult factors to assess in human studies has been the physiological contribution of chronic stressors to the development, response to treatment and prevention of breast cancer. In animal models, unrelenting exposure to the continuous stressor of social isolation can lead to hypervigilance. However, relatively lilffle is known about the relationship between chronic exposure to stressors, resulting behavioral changes, and related physiological consequences. McClintock and colleagues (Project 1) recently found that exposure to long-term social isolation increases both hypervigilance and susceptibility to spontaneous mammary gland tumors in the Sprague Dawley rat model. Recently, our laboratory (Project 4) has described a novel anti-apoptotic signaling pathway in mammary epithelial cells and breast cancer cell lines that is initiated by glucocorticoid receptor (GR) activation. Among the stress hormones, glucocorticoids are an important category of deregulated hormones in humans and animals subjected to chronic stressors. Interestingly, although baseline corticosterone levels are reduced in rodent models of chronic stress, the initial corticosterone response of these animals to acute stressors is normal while the period of time it takes for corticosterone levels to return to baseline is prolonged. We hypothesize that the altered hypothalamic-pituitary-adrenal (HPA) axis resulting from exposure to the chronic stressor of social isolation may feedback to increase GR receptors in the mammary gland, while the prolonged corticosterone response to acute stressors will lead to increased activation of the GR pathway. The expected consequence of GR activation in the ductat epithelium of the mammary gland is to promote cell survival and inhibit apoptosis of premalignant, rapidly proliferating mammary epithelial cells. Likely acting in concert with additional hormonal changes induced by chronic stress and accompanying hypervigilance, GR-induced loss of apoptosis may be an important mechanism leading to the mammary gland hyperplasia that is seen in our preliminary rodent data. We therefore propose to test the hypothesis that social isolation and resulting hypervigilance leads to a significant increase in GR-mediated mammary epithelial cell survival signaling. Three experimental aims will be pursued. First, we wil lexamine the possible correlation of social isolation, hypervigilance and corticosterone secretion with evidence of increased GR expression and activation in two rodent models of breastcancer. Second, we will determine whether chemotherapy response is altered by chronic stress in these two well-established rodent models. Third, the effect of stress and hypervigilance on patterns of corticosterone secretion, GR signaling and response to chemoprevention will be evaluated. Taken together, the proposed experiments will help to develop valuable preclinical models for studying the impact of stress on breastcancer incidence, treatment and prevention in populations subjected to unmitigated stressors.